Exercise is a substantial stress and when performed in a hot environment, thermal injury and mortality are exacerbated. Heat stroke is the most catastrophic form of thermal injury and is characterized by cardiovascular collapse and multi-organ system failure. While the earliest events are unknown, evidence is accumulating that alterations in a critical target tissue are pivotal in the pathogenesis of heat stroke. The concept of a critical target tissue suggests differences in tissue stress tolerance. Because cells respond to stress by synthesizing a family of proteins termed heat shock proteins, the synthesis of the most highly heat responsive HSP family member -- HSP70, a molecular chaperone -- may serve as a biomarker for those tissues at risk in heat stress. The applicant hypothesizes that (a) the accumulation of HSP70 will identify those tissues most susceptible in whole animal hyperthermia; (b) hyperthermic stress is mediated in part by intracellular oxyradical generation; and (c) differences in the regulation of HSP70 in response to hyperthermia and oxidant stress are based upon post- transcriptional mechanisms. This proposal combines animal, cell, and molecular experiments to evaluate a common mechanism by which both whole animals and isolated cells may respond to heat stress. This integrated approach will provide information on the biochemistry and molecular biology of the early and potentially responsible events in heat injury -- in particular, the cellular and molecular mechanisms of control of HSP synthesis and its relationship to heat injury and acclimation in animals. This information could lead to new insights into molecular mechanisms of exercise-induced injury.